While numbers of tobacco-associated head and neck squamous cell carcinoma (HNSCC) sharply declined during the latter half of the 20th century, incidence of human papillomavirus (HPV)-associated HNSCC specifically oropharyngeal cancer (OPC), which like cervical cancer is currently thought to be predominantly an HPV-related cancer, has sharply increased. The number of persons exposed to HPV is far greater than the number who ultimately develop HPV-related cancers, thus heritable genetic factors as well as the interplay between genetic and environmental factors likely modulate observed inter-individual differences in risk. However, the specific immune-related genetic variants helping to modulate individual susceptibility are largely unknown. We hypothesize that variation in immune-related genes likely plays a role in the host susceptibility to development of OPC in the VA population. We further hypothesize that integrative bioinformatic analysis can be used to identify gene variants associated with increased risk of OPC, particularly in those with confirmed HPV infection. Although immune genes are expected to play a large role in virally-associated OPC, they may also play a role in risk of non-oropharynx head and neck squamous cell cancer (non-OPC HNSCC) which is overwhelmingly associated with smoking and alcohol abuse because both OPC and non-OPC HNSCC increase 1) chronic inflammation, a pro-carcinogenic state, and 2) are associated with immune evasion associated with oncogenesis which both impact cancer risk partially by mediating immune gene signaling. In the first Aim we will use validated methods to phenotype four distinct study cohorts within the MVP: OPC both overall and among those with HPV infection (HPVOPC), non-OPC HNSCC, and matched cancer-free controls. In order to identify confirmed HPV-related OPC (HPVOPC), we will obtain p16 immunohistochemistry data from pathology reports via chart review. We will include in our source population to select both cases and controls all participants in MVP with genetic array data. We will define (1) demographics (e.g., age, gender, race/ethnicity from CDW) and (2) clinical comorbidities and environmental and behavioral risk behaviors (e.g., BMI, diabetes, smoking, and alcohol use from CDW and MVP surveys). Four randomly selected controls with a VA visit in the same year the case was first identified (index date) will be frequency matched by age, race/ethnicity, gender, geographic region, year of first VA use in study period, and first VA enrollment during study period for each cancer group. In the second Aim we will perform parallel integrative genetic analysis of the association between polymorphisms in multiple pre-selected immune genes and all OPC, HPVOPC (subset that are pathology- confirmed HPV positive by p16 immunohistochemistry), and non-OPC HNSCC. We will identify shared and/or unique risk variants across HPVOPC, OPC overall and non-OPC HNSCC. We will also assess for gene-gene and gene-environmental interaction to help further elucidate potential mechanistic pathways by which immune- related genes singly, jointly and in conjunction with key established risk factors like smoking influence risk of both virally-mediated (OPC/HPVOPC) and non-virally mediated (non-OPC HNSCC) cancers. Identification of genotypes modifying risk of HPV-related cancers like OPC has near-time translational implications as it could serve as the basis for enhanced screening and surveillance programs to identify HPV infected veterans at increased risk of disease progression and may identify potential novel disease modifying therapeutic targets. Additionally, our study will also provide novel data on immune gene-gene and immune gene-environment interactions that may identify novel therapeutic targets to be evaluated in future research on both OPC and non-OPC HNSCC.